Imagine five doctors simultaneously assessing one person's health. One primarily focuses on the immune system, the second on metabolism, the third on mitochondrial function, and the fourth on the cells' ability to repair DNA damage. Each draws correct conclusions but sees only a part of the overall picture.
It seems epigenetic clocks work in a similar way.
These algorithms determine biological age based on DNA methylation marks and have long been considered among the best tools for assessing organismal aging. However, scientists have been puzzled by a paradox for a long time: models built on virtually the same molecular data predict disease risk, aging speed, and even lifespan differently.
To understand the reason, researchers from the University of Southern California analyzed data from 3,227 participants in the large American Health and Retirement Study. For each volunteer, DNA methylation and the transcriptome—the complete picture of gene activity—were studied simultaneously. The scientists then compared the five most well-known biological age models: Horvath, Hannum, PhenoAge, GrimAge, and DunedinPACE.
It turned out that each of these algorithms reflects its own aspect of the aging process. Some clocks are more strongly linked to immune system genes and inflammation, others to mitochondrial function, and still others to DNA repair mechanisms. There were far fewer common biological pathways among them than unique ones.
This means that aging cannot be represented as a single process that occurs uniformly in all people. Rather, dozens of interconnected processes occur simultaneously within the body, and each of them can accelerate according to its own scenario.
To test this idea, the researchers created new aging measures based on gene activity—Transcriptomic Aging Gene Scores (TAGS). In some cases, they were even more accurately linked to age-related diseases and the risk of death than the epigenetic clocks themselves. At the same time, TAGS do not replace existing models but complement them, allowing for the observation of ongoing changes from multiple perspectives simultaneously.
The most interesting conclusion of this work goes far beyond the epigenetic clocks themselves. The study shows that an organism cannot be described by a single indicator. Biological age is not a single number, but a multidimensional picture, in which the functioning of the immune system, energy metabolism, DNA repair, gene activity, and many other processes are intertwined.
This is precisely why different epigenetic clocks do not contradict each other. They are like several maps of the same territory: each shows its own dimension of reality, and together they form a much more complete picture.
This perspective reflects an increasingly important idea in modern biology—the principle of integrity. An organism is not a collection of separate organs or molecules, but a single living system where changes in one part inevitably affect all others. The better we understand these interconnections, the more accurately we can determine not only how much a person is aging, but also why it is happening specifically to them.
Perhaps this is where the next stage of longevity medicine begins. Instead of searching for a single universal "aging indicator," scientists are gradually moving towards a multidimensional model of a person, where health is viewed as the result of the coordinated work of multiple biological systems. Such an approach will allow not only to measure biological age but also to understand which processes need support first and to select truly personalized methods of prevention and treatment.
Beyond the results of the study itself lies another important thought. Complex living systems do not reveal their laws if viewed from only one perspective. Only by combining different levels of information—from gene activity to immune system function and metabolism—can a holistic picture be seen. And perhaps, it is this multidimensional view that will be the next step not only in understanding aging but also in understanding the very nature of life.
